Jorumycin is a natural compound isolated from the skin and from the mucus of the Pacific nudibranch Jorunna funebris (Fontana A., et al., Tetrahedron (2000), 56, 7305-8). In addition, the family of renieramycins is disclosed as being isolated from sponges and tunicates (James M. F. et al. J. Am. Chem. Soc. (1982), 104, 265-269; Oku N., et al. Journal Natural Products (2003), 66, 1136-9). Safracin and saframycin compounds are disclosed in Manzanares I., et al. Curr. Med. Chem. Anti-Cancer Agents (2001), 1, 257-276, as well as in WO 00/18233 and WO 01/87894.
Because of the detailed description provided in such references and citations therein, the structural characterizations of such compounds are not given again explicitly herein; any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources. At least two of such compounds, PM00104 and PM00121 will be referred to specifically herein to illustrate features of this invention.
PM00104 and PM00121 are synthetic alkaloids related to jorumycin and renieramycins, and also to safracin and saframycin compounds. They show the following chemical structures:

A pharmaceutical composition comprising PM00104 or PM00121 together with a pharmaceutically acceptable carrier is claimed in WO 01/87894.
PM00104 has demonstrated a significant in vitro activity against solid and non-solid tumor cell lines as well as significant in vivo activity in several xenografted human cell lines in mice, such as breast and prostate. Preliminary insights into the mechanism of action of PM00104 suggested cell cycle changes, DNA binding properties and transcriptional inhibition. In addition, clinical phase I studies are currently ongoing with PM00104. For further activity data details of PM00104 and PM00121 see WO 01/87894
PM00104 and PM00121, as well as related compounds, are complex chemical entities, as revealed by their structural features. In addition, they exhibit limited aqueous solubility, and their stability, particularly in biocompatible forms and formulations, is difficult to predict and achieve. These characteristics challenge the ordinary skills and conventional methodologies in this technology, particularly when it comes to the preparation of formulations of these compounds that are to be readily used for medical purposes. Such uses preferably rely on formulations whose characteristics include one or more of the following: biocompatibility, stability under ambient conditions, or under conditions that are as near to ambient conditions as possible, with a shelf life that is as long as possible, and easy reconstitutability to form reconstituted solutions that are as stable under ambient, or near ambient conditions, for as long as possible.
In view of the potential of these compounds as antitumoral agents, there is a need to provide a formulation that can solve problems that conventional formulations and manufacturing methodologies do not address or do not completely solve. These problems include the problem of stability of these compounds. Embodiments of PM00104, PM00121 and related compounds formulations should preferably exhibit favourable freeze-drying properties, should preferably be susceptible of ready reconstitution, and they should preferably exhibit dilution properties, such as upon dilution with infusion fluid, while presenting as many of the desirable characteristics of formulations for medical use as referred to herein. As indicated above, embodiments of these formulations should be stable during long term storage. In addition, the formulation and its manufacturing methodology should satisfy biocompatibility standards and should thus allow for the effective use of a formulation vehicle that is non-toxic, at least at the concentrations used for infusion.
A general review of excipient-drug interactions in parental formulations is provided by Akers M. J., in Journal of Pharmaceutical Sciences, 91, 2002, 2283-2300. This reference provides, inter alia, a section on bulking agents and lyoprotectants, including this subject matter in the context of lyophilisation.
It is envisaged that the methodologies and formulations developed in the context of this invention are applicable to other related compounds, in addition to PM00104 and PM00121.